ES2804101T3 - 4-amino-imidazoquinoline compounds - Google Patents

Abstract

A compound of formula ** (See formula) ** wherein R1 is C1-7 alkyl or C1-7 alkoxy-C1-7 alkyl; R2 is selected from the group consisting of hydrogen, halogen, C1-7 alkoxycarbonyl-C1-7 alkyl and C1-7 alkoxycarbonyl-C2-7 alkenyl; R3 is hydrogen; R4 is selected from the group consisting of -O- (CH2) m-NHR5 and -O- (CO) - (CH2) n-NHR6, where m is 2, n is 1, R5 is hydrogen, and R6 is hydrogen ; or pharmaceutically acceptable salts thereof.

Description

DESCRIPTION

4-amino-imidazoquinoline compounds

FIELD OF THE INVENTION

The present invention relates to novel 4-amino-imidazoquinoline derivatives having pharmaceutical activity, their manufacture, pharmaceutical compositions containing them and their potential use as medicaments.

In particular, the present invention relates to compounds of the formula

wherein R1 through R4 and X are as described below, or pharmaceutically acceptable salts thereof.

The compounds are TLR agonists. In particular, the compounds are agonists of TLR7 and / or TLR8 and more particularly, agonists of both TLR7 and TLR8 receptors. Therefore, they can be useful for the treatment and prevention of cancer, autoimmune and infectious diseases. For example, they can be useful in a vaccine against diseases such as cancer, autoimmune or infectious diseases.

Toll-like receptors (TLRs) are a family of membrane-spanning receptors that are expressed on cells of the immune system as dendritic cells, macrophages, monocytes, T lymphocytes, B lymphocytes, NK lymphocytes, and mast cells, but also on cells. endothelial and epithelial. (Kawai et al., Immunity, 2011, 34, 637-650, Kawai et al., Nat. Immunol., 2010, 11, 373-384). TLRs that recognize bacterial and fungal components are expressed on the cell surface (i.e. TLR1, 2, 4, 5, and 6), while others that recognize viral or microbial nucleic acids such as TLR3, 7, 8, and 9 are localized to the endolysosomal / phagosomal membrane. (Henessy et al. Nat. Rev. Drug Discovery 2010, 9, 293-307). Activation of TLR results in the induction and release of pro-inflammatory cytokines, depending on the specific activation sequence and response of the specific TLR and the specific cell type. Both TLR7 and TLR8 are expressed on monocytes and macrophages, with TLR7 also highly expressed on plasmacytoid dendritic cells and TLR8 on myeloid dendritic cells and mast cells. Both receptors are activated by ssRNA and their activation stimulates the production of cytokines such as IL-6, IL-12, TNF-a and IFN-y and additional costimulatory molecules and chemokine receptors. Depending on the cell type, type I interferons, IFNa (from plasmacytoid dendritic cells) and IFNp, are also produced by cells upon activation with TLR7 / 8 agonists (Uematsu et al., J. Biol. Chem., 2007, 282, 15319-15323).

Small molecule agonists for both the TLR7 and TLR8 receptors, as well as modified analogs for use as adjuvants or vaccine conjugates have been identified in many patents (i.e. WO1992015582, US 2003187016, WO 2005076783, WO2007024612, WO2009111337, WO2010093436, WO2011017611, WO2011068233, WO2011139348, WO2012066336, WO2012167081, WO2013033345, WO2013067597, WO2013166110 and US2013202629). Clinical experience has been obtained using exclusively TLR7 agonists. A number of the first compounds have shown antiviral and anticancer properties. For example, the TLR7 agonist imiquimod (ALDARA ™) is approved by the US Food and Drug Administration as a topical agent for the treatment of condylomata acuminata, superficial basal cell carcinoma, and actinic keratosis. However, the systemic application of early TLR7 agonists such as resiquimod has been discontinued due to the intolerable cardiotoxicity observed after global chemokine stimulation to therapeutic levels (Holldack, Drug Discovery Today, 2013, 1-4). Knowledge about TLR8 agonists is less advanced and is mainly limited to data with early mixed TLR7 / 8 agonists such as resiquimod and more recently to compounds disclosed by VentiRX Pharmaceuticals (i.e. WO2010054215, WO2012045090). At present, there is still a need for additional small molecule TLR7 and TLR8 agonists, specifically those with enhanced potency.

The present invention is directed to 1H-imidazo [4,5-c] quinolin-4-amine-2-methylpropan-2-yloxy derivatives with improved cellular potency over known TLR7 and / or TLR8 agonists of this type for its use in the cancer treatment, preferably solid tumors and lymphomas, and for other uses that include the treatment of certain dermatopathies or skin diseases, such as atopic dermatitis, the treatment of infectious diseases, preferably viral diseases, and for use as adjuvants in formulated vaccines for use in treating cancer or desensitizing receptors by continuous stimulation in treating autoimmune diseases.

Specifically, the present invention discloses 1H-imidazo [4,5-c] quinolin-4-amine-2-methylpropan-2-yloxy derivatives that are derivatized directly at the tertiary alcohol with an aminoethyl or glycine moiety. Due to the low reactivity of tertiary alcohol, these derivatives had obviously eluded early attempts at synthesis. Surprisingly, these new compounds possess a high cellular potency in TLR7 that is comparable to or even better than resiquimod itself, while the close analogs that were initially described such as 1- (2- (2-aminoethoxy) ethyl) -2 - (Ethoxymethyl) -7H-imidazo [4,5-c] quinolin-4-amine (example 69 of US20030187016) do not show the required activity. Furthermore and surprisingly, the 1H-imidazo [4,5-c] quinolin-4-amine-2-methylpropan-2-yloxy derivatives described are strong agonists of the TLR8 receptor with comparable or superior potency to the agonists of Hitherto disclosed TLR8 from other chemical classes and greatly improved over resiquimod itself. Thus, the compounds of the present invention satisfy the need to activate both TLR7 and TLR8 receptors with enhanced potency.

SUMMARY OF THE INVENTION

The present invention relates to 4-amino-imidazoquinoline derivatives of the formula

in which

R1 is C ^1-7 alkyl or C1-7 alkoxy-C ^1-7 alkyl;

R2 is selected from the group consisting of hydrogen, halogen, C ^1-7 alkoxycarbonyl-C ^1-7 alkyl and C 1-7 alkoxycarbonyl-C 2-7 alkenyl;

R3 is hydrogen;

R4 is selected from the group consisting of

-O- (CH ² ) m-NHR5 and

-O- (CO) - (CH ² ) n-NHR6,

in which

m is selected from 2,

n is selected from 1,

R5 is selected from the group consisting of hydrogen and

R6 is selected from the group consisting of hydrogen,

or pharmaceutically acceptable salts thereof.

The invention also relates to processes for the manufacture of compounds of formula I.

The invention also relates to pharmaceutical compositions comprising a compound of formula I as described above and a pharmaceutically acceptable carrier and / or adjuvant.

Another aspect of the invention is the use of compounds of formula I as active therapeutic principles for the treatment of diseases that may be mediated with TLR agonists, in particular TLR7 and / or TLR8 agonists, more in particular, TLR7 and TLR8 receptors. Thus, the invention relates to a method for treating a disease that can be mediated with TLR agonists such as, for example, cancer and autoimmune or infectious diseases.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the present invention pertains. Additionally, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention.

The nomenclature used in this application is based on the IUPAC systematic nomenclature, unless otherwise indicated.

The term "compound (s) of this invention" and "compound (s) of the present invention" refer to compounds of formula I and solvates or salts thereof (eg, pharmaceutically acceptable salts).

The term "substituent" indicates an atom or group of atoms that replace a hydrogen atom in the original molecule.

The term "halogen" refers to fluorine, chlorine, bromine, and iodine, with fluorine, chlorine, and bromine of particular interest. More particularly, halogen refers to fluorine and chlorine.

The term "alkyl", alone or in combination with other groups, refers to a straight or branched chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, in particular one to sixteen carbon atoms, more in particular of one to ten carbon atoms. The term "C ^1-10 alkyl" refers to a straight or branched chain monovalent saturated aliphatic hydrocarbon radical of one to ten carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl , sec-butyl, tere-butyl, pentyl, 1,1,3,3-tetramethylbutyl. More particularly, the term "alkyl" also encompasses lower alkyl groups as described below. The term "lower alkyl" or "C ^1-7 alkyl", alone or in combination, means a straight chain or branched chain alkyl group with 1 to 7 carbon atoms, in particular a straight chain or branched alkyl group with from 1 to 6 carbon atoms and more in particular a straight or branched chain alkyl group with from 1 to 4 carbon atoms. Examples of ^{straight and branched chain C 1-7} alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tere-butyl, isomeric pentyl, isomeric hexyl and isomeric heptyl, in particular methyl and ethyl.

The term "lower alkenyl" or "C ^2-7 alkenyl" means a straight chain or branched chain hydrocarbon residue comprising an olefinic bond and from 2 to 7, in particular from 3 to 6, more in particular from 3 to 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl, in particular ethenyl.

The term "lower alkoxy" or "C ^1-7 alkoxy" refers to the group R'-O-, where R 'is lower alkyl and the term "lower alkyl" has the previously given meaning. Examples of lower alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy, in particular methoxy.

The term "lower alkoxycarbonyl" or "C ^1-7 alkoxycarbonyl" refers to the group -COOR, where R is lower alkyl and the term "lower alkyl" has the previously given meaning. Lower alkoxycarbonyl groups of particular interest are methoxycarbonyl or ethoxycarbonyl.

The term "lower alkoxycarbonylalkyl" or "C ^1-7 alkoxycarbonyl-C 1-7 alkyl" refers to lower alkyl groups as defined above in which at least one of the hydrogen atoms of the lower alkyl group is replaced by an alkoxycarbonyl group. lower. Among the particular interesting alkoxycarbonyl-lower alkyl groups is - (CH ² ) ² -Co OC ² Hs.

The term "lower alkoxycarbonylalkenyl" or "C 1-7 alkoxycarbonyl-C ^2-7 alkenyl" refers to lower alkenyl groups as defined above in which at least one of the hydrogen atoms of the lower alkenyl group is replaced by an alkoxycarbonyl group. lower. Among the particular interesting lower alkoxycarbonyl-alkenyl groups is - (CH ² ) ² -COOC ² Hs.

The term "pharmaceutically acceptable" indicates an attribute of a material that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.

The compounds of formula I can form pharmaceutically acceptable salts. The term "sales pharmaceutically acceptable "refers to salts that retain the biological efficacy and properties of free bases or free acids, which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. Salts are for example acid addition salts of compounds of formula I with physiologically compatible mineral acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids, such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, malonic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, succinic acid or salicylic acid. In addition, they can be prepared r pharmaceutically acceptable salts from the addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including natural substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine. , ethanolamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, piperazine, W-ethylpiperidine, piperidine, and polyamine resins. The compound of formula I can also be in the form of zwitterions. The pharmaceutically acceptable salts of compounds of formula I of particular interest are the sodium salts or salts with tertiary amines.

The compounds of formula I can also be solvated, for example hydrated. The solvation can be effected in the course of the manufacturing process or it can take place, for example, as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration). The term "pharmaceutically acceptable salts" also includes physiologically acceptable solvates.

The term "agonist" indicates a compound that enhances the activity of another compound or receptor site as defined for example, in "The Pharmacological Basis of Therapeutics, by Goodman and Gilman, 7th ed." on page 35, Macmillan Publ. Company, Canada, 1985. A "full agonist" effects a complete response while a "partial agonist" effects a less than complete activation even when occupying the entire receptor population. An "inverse agonist" produces an effect opposite to that of an agonist, although it binds to the same receptor binding site.

The term "mean maximum effective concentration" (EC ⁵⁰ ) indicates the plasma concentration of a particular compound required to obtain 50% of the maximum of a particular effect in vivo.

The term "therapeutically effective amount" indicates an amount of a compound of the present invention which, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates, or eliminates one or further symptoms of the particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, disease state being treated, the severity or disease treated, the age and relative health of the subject, the route and manner of administration, the judgment of the medical specialist or veterinarian, and other factors. .

In detail, the present invention relates to compounds of formula

in which

R1 is C ^1-7 alkyl or alkoxy C i ^-7 C ^1-7 -alkyl;

R2 is selected from the group consisting of hydrogen, halogen, C ^1-7 alkoxycarbonyl Cwalquilo C ^1-7 alkoxycarbonyl and C ^2-7 -alkenyl;

R3 is hydrogen;

R4 is selected from the group consisting of

-O- (CH ² ) m-NHR5 and

-O- (CO) - (CH2) n-NHR6,

in which

m is selected from 2,

n is selected from 1,

R5 is selected from the group consisting of hydrogen and

R6 is selected from the group consisting of hydrogen

or pharmaceutically acceptable salts thereof.

In one aspect, the invention relates to compounds of formula I, wherein R1 is C1-7-alkyl C ^1-7. More in particular, R1 is ethoxyethyl.

In another aspect, the invention also relates to compounds of formula I, in which R4 is -O- (CO) - (CH ² ) n-NHR6 and in which n is 1 or 2 and in which R6 is hydrogen .

In a particular aspect, the invention relates to compounds of formula I, in which R2 is hydrogen.

The particular compounds of formula I according to the invention are the following:

1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine,

1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl) -2-methylpropan-2-yl 2- aminoacetate,

(E) -3- [4-amino-1- [2- (2-aminoethoxy) -2-methylpropyl] -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7-yl] prop Ethyl -2-enoate, 3- (4-amino-1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7- yl) ethyl propanoate, 3- (4-amino-1- (2- (2-aminoacetoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7-yl ) ethyl propanoate, 1- (2- (2-aminoethoxy) -2-methylpropyl) -2-pentyl-1H-imidazo [4,5-c] quinolin-4-amine,

1- (2- (2-aminoethoxy) -2-methylpropyl) -7-bromo-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine,

or pharmaceutically acceptable salts thereof.

In particular, the invention relates to the following compounds of formula I:

1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine,

or pharmaceutically acceptable salts thereof.

More particularly, the invention relates to compounds of formula I selected from the group consisting of 1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1- 2-aminoacetate yl) -2-methylpropan-2-yl,

Ethyl 3- (4-amino-1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7-yl) propanoate, and pharmaceutically acceptable salts thereof.

In particular, the invention relates to the following salts of compounds of formula I:

Ethyl 3- (4-amino-1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7-yl) propanoate hydrochloride ,

1- (2- (2-aminoethoxy) -2-methylpropyl) -7-bromo-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine,

or pharmaceutically acceptable salts thereof.

It will be appreciated that the compounds of general formula I in the present invention can be derivatized into groups functional to provide derivatives that can be converted back to the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives, which can produce the parent compounds of general formula I in vivo are also within the scope of the present invention.

Another aspect of the present invention is the process for the manufacture of compounds of formula I as defined above, which process comprises

a) reacting a compound of formula II

wherein R1, R2 and R3 are as defined herein above and GP is a protecting group, with a compound of formula III

where m is as defined herein above, under basic conditions, and remove the GP and Boc protecting groups under acidic conditions to obtain a compound of formula I-a

wherein R1 to R3 and m are as defined herein above, and optionally, further coupling the compound of formula Ia with an alcohol or acid of formula R5-OH or an aldehyde of formula R5 = O to obtain a compound of formula Ic

wherein R1 to R3, m and R5 are as defined hereinbefore, and, if desired, converting the obtained compound into a pharmaceutically acceptable salt, or

b) reacting a compound of formula Il-a

wherein R1, R2 and R3 are as defined herein above and GP 'is a protecting group, with a carboxylic acid of formula IV

where n is defined as hereinbefore and GP "is a protecting group, in the presence of an esterifying agent, and removing the protecting groups GP 'and GP" with a mild reducing agent to obtain a compound of formula I-b

wherein R1 to R3 and n are as defined herein above, and optionally, further coupling the compound of formula Ia with an alcohol or acid of formula R6-OH or an aldehyde of formula R6 = O to obtain a compound of formula Id

wherein R1 to R3, m and R6 are as defined hereinbefore, and, if desired, converting the obtained compound into a pharmaceutically acceptable salt.

In particular, a suitable GP protecting group is a trityl (TRT) selected amino protecting group, or double protection using an isoindoline-1,3-dione, bis-benzyl or bis-carboxybenzyl (bis-Z) protecting group .

"Under basic conditions" means the presence of a base such as sodium hydride or potassium tert-butylate. The reaction is carried out in a suitable solvent such as, for example, W, W-dimethylformamide (DMF), dimethylacetamide (DMA), dichloromethane or dioxane, at temperatures between 0 ° C and room temperature.

"Remove GP and Boc protecting groups under acidic conditions" means treating the acid-protected compound in a suitable solvent, for example, trifluoroacetic acid (TFA) in a solvent such as dichloromethane (DCM) can be employed.

Suitable protecting groups GP 'and GP "are protecting groups that form a cyclic ring with the nitrogen atom of the amino group. In particular, GP' or GP" together with the nitrogen atom to which they are attached. they form an isoindoline-1,3-dione or represent a bis-benzyl or bis-carboxybenzyl protecting group.

An esterification agent is a compound that facilitates an esterification reaction. A particular esterifying agent is W, W-diisopropyl-carbodiimide. The reaction is carried out, in particular, in an inert solvent, such as DCM.

"Remove the protecting groups GP 'and GP" with a mild reducing agent ", in particular, means treating the protected compound with hydrazine / water in an inert solvent, such as THF.

The invention further relates to compounds of formula I as defined above obtainable according to a process as defined above.

The synthesis of the compounds with the general structure I can be achieved, for example, according to the following schemes. Unless otherwise indicated, R1 to R3 and X are as defined above. A route to the starting materials of formula AG is provided in Scheme 1, and the route has been exemplified in WO 2013/033345 (Univ. Of Minnesota).

Compounds AB can be obtained from suitably substituted AA orthoesters by condensation with 2-amino-propanedinitrile and 1-amino-2-methyl-propan-2-ol in an inert solvent, such as THF in the presence of a base. , such as triethylamine. Suitable AA substituted orthoesters are commercially available, can be synthesized by one of ordinary skill in the art, or have been exemplified in the experimental part. Compounds AC can be obtained from compounds AB by diazotization / iodination as is known in the art; specifically using diiodomethane as the source of iodide and isoamylnitrite as the source of nitrite in an inert solvent such as chloroform at temperatures from 0 ° C to the boiling point of the solvent, preferably at a temperature of 80 ° C.

Compounds of formula AC can be coupled with compounds of formula AD where M indicates a metal leaving group and R 'indicates hydrogen and / or a suitable protecting group, by procedures known in the art, to give compounds of formula AE. Suitable metal leaving groups can be boronic acids, boronate esters and trifluoroborates, but also tin- or zinc-based leaving groups. In particular, boronic acids or boronate esters can be used in Suzuki-Miyaura type couplings using a palladium catalyst, such as Pd (OAc) ² in the presence of triphenylphosphine, in an inert solvent, such as DME, together with a suitable base. , as sodium carbonate. The reaction temperature can vary from room temperature to the boiling point of the solvent, with room temperature being a suitable choice in many cases. If compounds AE are protected at the amino group of aniline (an R 'other than H), deprotection to provide compounds of type AF can be accomplished by procedures known in the art, with acid cleavage of the protecting group using TFA being an option. preferential.

Compounds of type AG can be obtained from compounds AF by thermal condensation (ring closure) in the presence of an acid catalyst. This can be achieved simply by heating the AF compounds in an inert solvent, such as dioxane, in the presence of an acid, such as HCl, for an appropriate time, for example, for 2 hours at 90 ° C.

After the procedure according to scheme 2, compounds AG can be used as starting material for the synthesis of compounds Ia where R4 is -O- (CH ² ) m-NH ² .

Compound BA can be obtained from AG by reaction with trityl chloride in the presence of a base in an inert solvent at elevated temperature with or without microwave irradiation. A suitable solvent based combination is, for example, triethylamine or DIEA and acetonitrile, especially if the reaction is carried out at elevated temperature in a microwave reactor.

Compounds of general formula BC can be obtained from compounds of general formula BA by reaction with Boc-sulfamidate BB in a suitable solvent such as DMF in the presence of a suitable base such as sodium hydride or potassium tert-butylate. The reaction is advantageously carried out at 0 ° C to room temperature.

Compounds of general formula Ia can be obtained from compounds of general formula BC by removing the protecting groups by treatment with acids in a suitable solvent. One such acid is TFA with or without additional DCM, used at room temperature.

After the procedure according to scheme 3, compound AG can be used as a starting material for the synthesis of compounds Ib where R4 is -O- (CO) - (CH ² ) n-NH ² .

Compound CA can be obtained from AG by introduction of a suitable GP protecting group by procedures known in the art. Such protecting groups can be, for example, isoindoline-1,3-dione (phthalyl). Specifically, compound CA can be reacted with phthaloyl chloride in the presence of a base, such as 1,4-diazabicyclo [2.2.2] octane, in an inert, high-boiling solvent, such as toluene, at elevated temperatures. to give a CA- type compound with isoindoline-1,3-dione as a protecting group.

Compound CC can be obtained from compounds CB and CA by esterification using one of the many procedures described in the art. Advantageously, said esterification can be achieved by combining CB and CA in an inert solvent, such as DCM, in the presence of W, W-diisopropyl-carbodiimide at elevated temperature. Suitable carboxylic acids CB are commercially available, can be prepared by procedures known in the art or have been exemplified in the experimental part.

Compounds of general formula Ib can be obtained from compounds of general formula CC by removal of protecting groups with procedures known in the art. Specifically, isoindoline-1,3-dione can be removed by treatment with hydrazine / water in an inert solvent, such as THF, at room temperature.

After the procedure according to scheme 4, compounds Ic and Id can be obtained from Ia or Ib by procedures known in the art, such as, for example, amide couplings (R5-OH or R6-OH are acidic) or reductive aminations (R5 = O or R6 = O are aldehydes) as explained in more detail in the experimental part.

Scheme 4

procedures

procedures

amide coupling

If one of the starting materials, the compounds of formula AA, AD, AG, DA, DB, DC or DD, contains one or more functional groups that are not stable or are reactive under the reaction conditions of one or more stages of reaction, appropriate protecting groups (GPs) can be introduced (as described, for example, in TW Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3rd edition) prior to critical stage applying procedures well known in the art. Such protecting groups can be removed at a later stage in the synthesis using standard procedures known in the art.

If one or more compounds of formula AA, AD, AG, DA, DB, DC or DD contain chiral centers, the compounds of formula I can be obtained as mixtures of diastereomers or enantiomers, which can be separated by procedures well known in the art. , for example, HPLC (chiral) or crystallization. You can separate the racemic compounds, for example, in their antipodes by means of diastereomeric salts by crystallization or by separation of the antipodes by specific chromatographic procedures using a chiral adsorbent or a chiral eluent.

As described hereinbefore, the compounds of formula I of the present invention can be used as medicaments for the treatment of diseases that are mediated by TLR agonists, in particular for the treatment of diseases that are mediated by TLR7 agonists. and / or TLR8, more particularly for the treatment of diseases that are mediated by TLR7 and TL8 agonists.

The compounds defined in the present invention are agonists of TLR7 and / or TLR8 receptors in in vitro cell assays. More particularly, the compounds of the present invention are agonists of both TLR7 and TLR8 receptors. Consequently, the compounds of the present invention are expected to be potentially useful agents in the treatment of diseases or medical conditions that can benefit from activation of the immune system by means of TLR7 and / or TLR8 agonists, more particularly in the treatment of diseases or medical conditions that can benefit from activation of the immune system through both TLR7 and TLR8 receptors. For example, the following diseases and conditions can be treated with compounds of the present invention.

The compounds of formula I of the present invention are useful in oncology, that is, they can be used in the treatment of common cancers including bladder cancer, head and neck cancer, prostate cancer, colorectal cancer, kidney cancer, cancer. breast cancer, lung cancer, ovarian cancer, cervical cancer, pancreatic cancer, colon cancer, stomach cancer, thyroid cancer, melanoma, skin and brain tumors, and malignancies affecting the bone marrow, such as leukemias and lymphoproliferative systems, such as Hodgkin's lymphoma and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic cancer and tumor recurrences, and paraneoplastic syndromes.

The compounds of formula I of the present invention are also useful in the treatment of autoimmune diseases. An "autoimmune disease" is a disease or disorder that arises from and is directed against an individual's own tissues or organs or a cosegregation or manifestation thereof or a condition resulting therefrom. "Autoimmune disease" can be an organ-specific disease (that is, the immune response is specifically directed against a system or apparatus such as the endocrine system, the hematopoietic system, the skin, the cardiorespiratory system, the digestive system, and the liver system, urinary tract, thyroid, ears, neuromuscular system, central nervous system) or a systemic disease that can affect multiple systems or systems (eg, systemic lupus erythematosus (SLE), rheumatoid arthritis, polymyositis). In a particular aspect, autoimmune disease is associated with skin, muscle tissue, and / or connective tissue.

Particular autoimmune diseases include autoimmune rheumatological disorders (such as, for example, rheumatoid arthritis, Sjogren's syndrome, scleroderma, lupus such as SLE and lupus nephritis, polymyositis / dermatomyositis, cryoglobulinemia, antiphospholipid antibody syndrome, and psoriatic arthropathy), autoimmune liver diseases (such as, for example, inflammatory bowel diseases, ulcerative colitis and Crohn's disease), autoimmune gastritis and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and celiac disease), vasculitis (such as, for example, non-ANCA-associated vasculitis and ANCA-associated vasculitis, including Churg-Strauss vasculitis, Wegener's granulomatosis, and microscopic polyangiitis), autoimmune neurological disorders (such as, for example, multiple sclerosis, opsoclonia-myoclonus syndrome, myasthenia gravis, neuromyelitis) optic itis, Parkinson's disease, Alzheimer's disease, and autoimmune polyneuropathies), kidney disorders (such as, for example, glomerulonephritis, Goodpasture's syndrome and Berger's disease), autoimmune dermatological disorders (such as, for example, psoriasis, urticaria, hives , pemphigus vulgaris, bullous pemphigoid and cutaneous lupus erythematosus), blood disorders (such as, for example, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, post-transfusion purpura, and autoimmune hemolytic anemia), atherosclerosis, uveitis (such as auditory, autoimmune diseases) inner ear disease and hearing loss), Behpet's disease, Raynaud's syndrome, organ transplantation, and autoimmune endocrine disorders (such as, for example, diabetes-related autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM), Addison's disease, and thyroid disease autoimmune (e.g. mplo, Graves' disease and thyroiditis)), allergic conditions and responses, food allergies, drug allergies, insect allergies, rare allergic disorders such as mastocytosis, allergic reaction, eczema including allergic or atopic eczema, asthma such as bronchial asthma and asthma autoimmune, conditions involving T-cell infiltration and chronic inflammatory responses:

The compounds of formula I of the present invention are also useful in the treatment of infectious diseases. Therefore, they may be useful in the treatment of viral diseases, in particular for diseases caused by infection with viruses selected from the group consisting of papillomaviruses, such as human papillomaviruses (HPV) and those causing condylomata acuminata, common warts and plantar warts, herpes simplex virus, molluscum contagiosum, hepatitis B virus (HBV), hepatitis C virus (HCV), dengue virus, smallpox virus, human immunodeficiency virus (HIV), cytomegalovirus (CMV), zoster and Chickenpox (VZV), rhinovirus, enterovirus, adenovirus, coronavirus (for example, SARS), flu, mumps, and parainfluenza virus. They may also be useful in the treatment of bacterial diseases, in particular for diseases caused by infection with bacteria selected from the group consisting of Mycobacterium such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium leprae. The compounds of formula I of the present invention may further be useful in the treatment of other infectious diseases, such as chlamydia, fungal diseases, in particular fungal diseases selected from the group consisting of candidiasis, aspergillosis and cryptococcal meningitis, and parasitic diseases such as Pneumocystis carnii, pneumonia, cryptosporidiosis, histoplasmosis, toxoplasmosis, Trypanosome infection, and leishmaniasis.

Thus, the term "diseases that are mediated by TLR agonists" means diseases that can be treated by activation of the immune system with TLR7 and / or TLR8 agonists such as cancer and infectious diseases. In particular, the term "diseases that are mediated by TLR agonists" means cancers or autoimmune diseases or infectious diseases selected from the group consisting of viral diseases, bacterial diseases, fungal diseases and parasitic diseases. In a particular aspect, the term "which are mediated by TLR agonists" refers to cancer selected from the group consisting of bladder cancer, head and neck cancer, prostate cancer, colorectal cancer, kidney cancer, breast cancer. , lung cancer, ovarian cancer, cervical cancer, pancreatic cancer, colon cancer, stomach cancer, thyroid cancer, melanoma, brain and skin tumors, and malignancies affecting the bone marrow, such as leukemias and bone marrow lymphoproliferatives, such as Hodgkin's lymphoma and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic cancer and tumor recurrences, and paraneoplastic syndromes.

The invention also relates to pharmaceutical compositions comprising a compound of formula I as defined above and a pharmaceutically acceptable carrier and / or adjuvant. More specifically, the invention relates to pharmaceutical compositions useful for the treatment of diseases that are mediated by TLR agonists.

Furthermore, the invention relates to compounds of formula I as defined above for use as therapeutically active substances, in particular as therapeutically active substances for the treatment of diseases that are mediated by TLR agonists. In particular, the invention relates to compounds of formula I for use in the treatment of cancers or autoimmune diseases or infectious diseases selected from the group consisting of viral diseases, bacterial diseases, fungal diseases and parasitic diseases.

The invention further relates to the use of compounds of formula I as defined above for the treatment of diseases that are mediated by TLR agonists.

Furthermore, the invention relates to the use of compounds of formula I as defined above for the preparation of medicaments for the treatment of diseases that are mediated by TLR agonists. In particular, the invention relates to the use of compounds of formula I as defined above for the preparation of medicaments for the treatment of cancers or autoimmune diseases or infectious diseases selected from the group consisting of viral diseases, bacterial diseases, fungal diseases and diseases parasitic.

In another aspect, the compounds of formula I may be in combination with one or more additional treatment modalities in a regimen for treating cancer.

Combination therapy encompasses, in addition to the administration of a compound of the invention, the complementary use of one or more modalities that are effective in the treatment of cancer. Such modalities include, but are not limited to, chemotherapeutic, immunotherapeutic, anti-angiogenic agents, cytokines, hormones, antibodies, polynucleotides, photodynamic and radiation therapeutics. In a specific aspect, combination therapy can be used to prevent cancer recurrence, inhibit metastasis, or inhibit the growth and / or spread of the cancer or metastasis. As used herein, "in combination with" means that the compound of formula I is administered as part of a treatment regimen comprising one or more additional treatment modalities as mentioned above. Therefore, the invention also relates to a method for the treatment of cancer, which method comprises administering a therapeutically active amount of a compound of formula I in combination with one or more other pharmaceutically active compounds to a human or animal.

The compounds of formula I can be used alone or in combination with one or more additional treatment modalities in the treatment of autoimmune diseases.

Combination therapy encompasses, in addition to the administration of a compound of the invention, the complementary use of one or more modalities that help in the prevention or treatment of autoimmune diseases. Said Modalities include, but are not limited to, chemotherapeutic, immunotherapeutic, antiangiogenic agents, cytokines, hormones, antibodies, polynucleotides, photodynamic and radiation therapeutics. As used herein, "in combination with" means that the compound of formula I is administered as part of a treatment regimen comprising one or more additional treatment modalities as mentioned above. Therefore, the invention also relates to a method for the treatment of autoimmune diseases, which method comprises administering a therapeutically active amount of a compound of formula I in combination with one or more other pharmaceutically active compounds to a human or animal.

In another aspect, the compounds of formula I can be used alone or in combination with one or more additional treatment modalities in the treatment of infectious diseases.

Combination therapy encompasses, in addition to the administration of a compound of the invention, the complementary use of one or more modalities that help in the prevention or treatment of infectious diseases. Such modalities include, but are not limited to, antiviral agents, antibiotics, and antifungal agents. As used herein, "in combination with" means that the compound of formula I is administered as part of a treatment regimen comprising one or more additional treatment modalities as mentioned above. Therefore, the invention also relates to a method for the treatment of infectious diseases, which method comprises administering a therapeutically active amount of a compound of formula I in combination with one or more other pharmaceutically active compounds to a human or animal. PHARMACOLOGICAL TEST

The following tests were carried out to determine the activity of the compounds of formula I:

To test the activity of TLR8 and TLR7 cells, TLR8 or TLR7 human HEK-Blue, respectively, were used (Invivogen, San Diego, CA, E ^e. UU.) Transfected with a reporter construct SEAP (phosphatase embryonic alkaline secreted), in which the expression of the reporter is regulated by the NF- ^{k B} promoter after stimulation for 24 h. Reporter activity was determined using the Quanti Blue kit (Invivogen, San Diego, Ca, USA) at a wavelength of 640 nm.

^{EC 50} values were determined using Activity Base analysis (ID Business Solution, Limited).

The compounds according to formula I have an activity (EC ⁵⁰ value) in the above assay for human TLR8 in the range of 0.01 nM to 11 pM, more in particular, from 0.01 nM to 3 pM and in the above assay for human TLR7 in the range from 0.01 nM to 1 pM, in particular from 0.01 nM to 0.3 pM and more particularly from 0.01 nM to 0.1 pM.

For example, the following compounds showed the following EC ⁵⁰ values in the assay described above:

PHARMACEUTICAL COMPOSITIONS

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, for example, in the form of pharmaceutical preparations for enteric, parenteral or topical administration. The compounds of formula I and their pharmaceutically acceptable salts can be administered by systemic (eg parenteral) or local administration (eg topical or intralesional injection). In some cases, the pharmaceutical formulation is administered topically, parenterally, orally, vaginally, intrauterine, intranasally, or by inhalation. As described herein, certain tissues may be preferred targets for the TLR agonist. Therefore, administration of the TLR agonist to lymph nodes, spleen, bone marrow, blood, as well as virus-exposed tissue, are preferred administration sites.

In one aspect, the pharmaceutical formulation comprising the compounds of formula I or their pharmaceutically acceptable salts is administered parenterally. Parenteral routes of administration include, but are not limited to, transdermal, transmucosal, nasopharyngeal, pulmonary, and direct injection. Parenteral administration by injection can be by any parenteral injection route, including, but not limited to, intravenous (iv) routes, including rapid intravenous and infusion (eg, rapid or slow), intraperitoneal (ip), intramuscular (im) , subcutaneous (sc) and intradermal (id). Transdermal and transmucosal administration can be achieved, for example, by inclusion of a vehicle (eg, dimethyl sulfoxide, DMSO), by application of electrical pulses (eg, iontophoresis), or a combination thereof. A variety of devices for transdermal delivery are available that can be used. Formulations of the compounds of formula I suitable for parenteral administration are generally formulated in USP water or water for injections and may further comprise pH buffers, salts, bulking agents, preservatives, and other pharmaceutically acceptable excipients.

Transdermal administration is accomplished by application of a cream, rinse, or gel that can allow the TLR agonist to penetrate the skin and enter the bloodstream. Compositions suitable for transdermal administration include, but are not limited to, pharmaceutically acceptable suspensions, oils, creams, and ointments applied directly to the skin or incorporated into a protective vehicle such as a transdermal device (referred to as a "patch"). Examples of suitable creams or ointments can be found, for example, in the Physician's Desk Reference. Transdermal transmission can also be achieved by iontophoresis, for example using commercially available patches that deliver their product continuously through intact skin for periods of several days or longer. The use of this procedure allows the controlled transmission of pharmaceutical compositions in relatively large concentrations, allows the infusion of drugs in combination, and allows the contemporaneous use of an absorption promoter. Administration via the transdermal and transmucosal routes can be continuous or pulsatile.

Pulmonary administration is accomplished by inhalation, and includes routes of administration such as intranasal, transbronchial, and transalveolar routes. Formulations of compounds of formula I suitable for administration by inhalation are provided including, but not limited to, liquid suspensions to form aerosols as well as powder forms for dry powder inhalation delivery systems. Suitable devices for inhalation administration include, but are not limited to, atomizers, vaporizers, nebulizers, and dry powder inhalation administration devices. Other methods of administration to the respiratory mucosa include the administration of liquid formulations, such as by nasal drops. Administration by inhalation is preferably achieved in discrete doses (eg, via a metered dose inhaler), although infusion-like administration can be achieved through the use of a nebulizer.

The compounds of formula I and pharmaceutically acceptable salts thereof can also be administered orally, for example, in the form of tablets, coated tablets, lozenges, soft and hard gelatin capsules.

The production of the pharmaceutical preparations can be carried out in a manner that is known to any person skilled in the art by bringing the described compounds of formula I and their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenic administration form together with Therapeutically compatible, inert, non-toxic, solid or liquid carrier materials suitable and, if desired, customary pharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, lozenges and hard gelatin capsules. Suitable carrier materials for soft gelatin capsules are, for example, liquid and semi-solid vegetable oils, waxes, fats and polyols (depending on the nature of the active ingredient, however, no carrier may be required in the case of gelatin capsules soft). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar. Suitable carrier materials for injectable solutions are, for example, water, alcohols, polyols, glycerol, and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hydrogenated oils, waxes, fats, and liquid or semi-liquid polyols. The materials of Suitable carriers for topical preparations are glycerides, synthetic and semisynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Stabilizers, preservatives, wetting and emulsifying agents, consistency improving agents, flavor improving agents, salts for varying the osmotic pressure, buffering substances, solubilizers, colorants and masking agents and usual antioxidants are considered as pharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and individual condition of the patient and the mode of administration, and will of course be adjusted to the individual requirements in each particular case. For adult patients, a daily dosage of about 1 to 1000 mg, especially about 1 to 300 mg, is considered. Depending on the severity of the disease and the precise pharmacokinetic profile, the compound could be administered in one or more daily dosage units, eg, in 1 to 3 dosage units.

Pharmaceutical preparations practically contain about 1-500 mg, preferably 1100 mg, of a compound of formula I.

The following Examples C1 to C3 illustrate typical compositions of the present invention, but serve merely as representative thereof.

Example C1

Film-coated tablets containing the following ingredients can be made in a conventional manner:

Ingredients Per tablet

Core:

Compound of formula I 10.0 mg 200.0 mg

Microcrystalline cellulose 23.5 mg 43.5 mg

Hydrated lactose 60.0 mg 70.0 mg

Povidone K30 12.5 mg 15.0 mg

Sodium starch glycolate 12.5 mg 17.0 mg

Magnesium stearate 1.5 mg 4.5 mg

(Core weight) 120.0 mg 350.0 mg

Film coating:

Hydroxypropylmethylcellulose 3.5 mg 7.0 mg

Polyethylene glycol 6000 0.8 mg 1.6 mg

Talc 1.3 mg 2.6 mg

Iron oxide (yellow) 0.8 mg 1.6 mg

Titanium dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granules are mixed with sodium starch glycolate and magnesium stearate and compressed to provide nuclei of 120 or 350 mg respectively. The cores are lacquered with an aqueous solution / suspension of the aforementioned film coating.

Example C2

Capsules containing the following ingredients can be made in a conventional manner:

Ingredients Per Capsule

Compound of formula I 25.0 mg

Lactose 150.0 mg

Corn starch 20.0 mg

Talc 5.0 mg

The components are sieved and mixed and filled into size 2 capsules.

Example C3

Injectable solutions can have the following composition:

Compound of formula I 3.0 mg

Polyethylene glycol 400 150.0 mg

Acetic acid q.s. up to pH 5.0

Water for injections up to 1.0 ml

The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injections (part). The pH is adjusted to 5.0 with acetic acid. The volume is adjusted to 1.0 ml by adding the residual amount of water. The solution is filtered, filled into vials using an appropriate surplus, and sterilized.

The following examples serve to illustrate the present invention in more detail.

Examples

Example 1

1- (2- (2-am¡noethox¡) -2-methylpropyl) -2- (ethoxymethyl) -1H-m¡dazo [4.5-c1qu¡nol¡n-4-am¡ na

a) 1- (2- (ethoxymethyl) -4- (tritlamno) -1H-m¡dazo [4,5-c] quinolin-1-¡l) - 2-methylpropan-2-ol

4-amino-2- (ethoxymethyl) -a, α-dimethyl-1H-imidazo [4,5-c] quinoline-1-ethanol (CAN 144875-48-9, 1.6 g, 5.09 mmol ) with acetonitrile (60 ml) to give a white suspension. Then, triethylamine (1.77 ml, 12.7 mmol) and trityl chloride (1.7 g, 6.11 mmol) were added under argon with stirring. The reaction mixture was irradiated in a microwave reactor at 100 ° C for 30 minutes. After stirring the mixture, the product precipitated and was isolated by filtration at 0 ° C, washed with cold acetonitrile and dried to provide the title compound (2.37 g, 83%) as a white solid; MS (ESI): 557.5 (MH +).

b) Tere-butyl 2- (1- (2- (ethoxymethyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinolin-1-yl) -2-methylpropan-2-yloxy) ethylcarbamate

The 60% sodium hydride-in-oil dispersion (173 mg, 4.32 mmol) was combined with DMF (15 mL) to give a colorless suspension. The mixture was cooled to 0 ° C with stirring, and at this temperature a solution of 1- (2- (ethoxymethyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinolin-1 was added dropwise -yl) -2-methylpropan-2-ol (1.85 g, 3.32 mmol) in DMF (15 mL) over a period of 10 min. Then the reaction mixture was stirred for 1 hour at 0 ° C and for 30 minutes at room temperature to give a yellow solution. To this solution was added at 0 ° C 2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid 1,1-dimethylethyl ester (CAN 459817-82-4, 964 mg, 4.32 mmol ). The temperature was allowed to rise to room temperature and the mixture was stirred overnight. The mixture was poured into ice water and extracted with ethyl acetate. The organic layers were washed with water / brine (2: 1), combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (1.47 g, 63%) as a white foam; LCMS (UV peak area, ESI) 98.7%, 700.3850 (MH +).

c) 1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine

Tert-butyl 2- (1- (2- (ethoxymethyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinolin-1-yl) -2-methylpropan-2-yloxy) ethylcarbamate was combined (1.45 g, 2.07 mmol) with dichloromethane (DCM, 12 ml) to give a colorless solution. TFA (6.0 ml, 77.9 mmol) was added and the mixture was stirred for 3 hours at room temperature. The reaction mixture at 0 ° C was cooled, added solution of sodium hydroxide 2N (40 ml), and the basic solution was extracted with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-10% methanol in DCM) to give the title compound (0.62g, 83%) as a white solid; LCMS (UV peak area, ESI) 97.5%, 358.2238 (MH +).

Example 2

1- (4-amino-2- (ethoxymethyl) -1H-m¡dazo [4.5-c1quinolin-1-¡l) -2-methylpropan-2- 2-aminoacetate it

a) 2- (2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c1quinolin-4-yl) isoindoline-1,3-dione

4-Amino-2- (ethoxymethyl) -a, α-dimethyl-1H-midazo [4,5-c] quinolin-1-ethanol (CAN 144875-48-9, 3.0 g, 9.54 mmol) with toluene (21.0 ml) to give a white suspension. 1,4-Diazabicyclo [2.2.2] octane (3.21 g, 28.6 mmol) and phthaloyl chloride (1.65 ml, 11.5 mmol) were added with stirring and the reaction mixture was stirred at 110 ° C for 4 hours. After cooling, the mixture was diluted with ethyl acetate (300 ml) and washed with 1N hydrochloric acid . The phases were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. After stirring the residue with ethyl acetate (50 ml), the product precipitated, filtered and dried under vacuum (1.9 g). The mother liquor was concentrated and, after flash chromatography (silica gel, 50 g, 0% to 100% EtOAc in heptane), another batch of product (0.59 g) was provided. In total, 2.49 g (59%) of the title compound was isolated as a white solid; LC-MS (UV peak area, ESI) 96%, 445.2 (MH +).

b) 2- (1,3-dioxoisoindolin-2-yl) acetate 1- (4- (1,3-dioxoisoindolin-2-yl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl) -2-methylpropan-2-yl

2- (2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) - '/ H-imidazo [4,5-c] quinolin-4-yl) isoindoline-1,3-dione (1600 mg, 3.6 mmol), 1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic acid (CAN 4702-13-0, 2.22 g, 10.8 mmol) and 4- ( 1-pyrrolidinyl) -pyridine (800mg, 5.4mmol) with DCM (36ml) to give a white suspension. N, N'- diisopropylcarbodiimide (1.68 ml, 10.8 mmol) and molecular sieves were added. The reaction mixture was heated to 50 ° C and stirred for 2 hours and, after cooling, filtered. The filtrate was diluted with DCM (150 ml) and washed with 1N hydrochloric acid and water. The aqueous phases were extracted with DCM, the organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo.

Diisopropylurea was removed after trituration with DCM / methanol by filtration, the filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give a light yellow solid . Crystallization with DMSO gave a first batch of product (1.95 g), and the mother liquor after concentration and preparative HPLC another 0.13 g of product. In total, 2.08 g (91%) of the title compound was isolated as a white solid; Cl-MS (Uv peak area, ESI) 95.9%, 632.2157 (MH +). c) 1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl) -2-methylpropan-2-yl 2-aminoacetate

1- (4- (1,3-dioxoisoindolin-2-yl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] 2- (1,3-dioxoisoindolin-2-yl) acetate was combined quinolin-1-yl) -2-methylpropan-2-yl (300 mg, 475 pmol) with THF (5 ml) to give a white suspension. Hydrazine in water (1000 µl, 11.2 mmol) was added to this suspension and the solution was stirred for 0.75 hours at room temperature. The mixture was cooled to 0 ° C, 1N hydrochloric acid (30 ml) and DCM (50 ml) were added. The white precipitate was removed to (phthalylhydrazide) by filtration and the organic phase was discarded. The aqueous phase was lyophilized and the residue was joined with acetonitrile (20 ml) and DIEA (pH 10). After evaporation of the solvent, the residue was purified by preparative HPLC (Gemini NX 3u 50x4.6mm; acetonitrile / water / EtsN) to give the title compound (111mg, 63%) as a white amorphous solid; LC-MS (UV peak area, ESI) 99%, 372.4 (MH +).

Example 3

N- (2- (1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl) -2-methylpropan-2-yloxylethyl) nicotinamide

Nicotinic acid (11.4 mg, 92.3 pmol) was combined with DMF (1.0 ml) to give a colorless solution. TBTU (29.6 mg, 92.3 pmol) and DIeA (54.2 mg, 71.8 µl) were added to this solution. Finally, 1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine (30 mg, 83.9 pmol) was added and the reaction mixture was stirred for 1 hour at room temperature. Volatiles were removed under high vacuum at 40 ° C. The residue was dissolved in a mixture of ethyl acetate (5 ml) and methanol (0.5 ml). 1N sodium hydroxide solution (1.5 ml) was added and after a few minutes of stirring the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic phases were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel-NH2, 0% to 10% methanol in DCM) to give the title product (33 mg, 85%) as a white foam; LCMS (UV peak area, ESI) 88%, 463.2459 (MH +).

Example 4

N- (2- (1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl) -2-methylpropan-2-yloxy) ethyl) acetamide

1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine (32 mg, 89.5 pmol) was combined with DCM (1.0 ml) to give a colorless solution. Triethylamine (25.0 µl, 179 pmol) and acetyl chloride (7.00 µl, 98.5 pmol) were added to this solution and the reaction mixture was stirred 18 hours at room temperature. After concentrating the mixture in vacuo, the residue was purified by flash chromatography (silica gel-NH ² , 0% to 10% methanol in DCM) to give the title compound (19 mg, 53%) as a foam. White; LC-MS (UV peak area, ESI) 97%, 400.2348 (MH +).

Example 5

3- (2- (1- (4-amino-2- (ethoxymethyl) -1H-m¡dazo [4.5-c1qu¡nol¡n-1-¡l) -2-met¡ lpropan-2-¡lox¡) ethyllamine) propan-1-ol a) 2- (ethoxymethyl) -1- [2-methyl-2- [2- (3-trityloxypropylamino) ethoxy] propyl] -imidazo [4,5-c] quinolin-4-amine

1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine (50 mg, 140 pmol) and 3- ( Triphenylmethoxy) -propanal (CAN 67057-68-5; 44.3 mg, 140 pmol) with ethanol (500 µl) to give a light yellow suspension. The mixture was stirred for 2 hours at room temperature. Then, sodium borohydride (5.82 mg, 154 pmol) was added and stirring continued at room temperature overnight. The mixture was stirred with water (2 ml) and ethyl acetate (5 ml), dried by passage through a ChemElut® cartridge and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel-NH2, 0% to 100% ethyl acetate in heptane) followed by another flash chromatography (silica gel, 0-10% methanol in ethyl acetate) to give the title compound (10mg, 11%) as a yellowish gum; LC-MS (UV peak area, ESI) 89%, 658.5 (MH +).

b) 3- (2- (1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl) -2-methylpropan-2-yloxy) ethylamino) propan- 1-ol

2- (Ethoxymethyl) -1- [2-methyl-2- [2- (3-trityloxypropylamino) ethoxy] propyl] -imidazo [4,5-c] quinolin-4-amine (10 mg, 15.2 pmol) with DCM (1 ml) to give a colorless solution. TFA (100 µl, 1.3 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel-NH2, 0% to 30% methanol in ethyl acetate) to give the title compound (2.3 mg, 36%) as a colorless gum; LC-MS (UV peak area, ESI) 95.6%, 416.2661 (MH +).

Example 6

Tere 6- (2- (1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c1quinolin-1-yl) -2-methylpropan-2-yloxy) ethylamino) -6-oxohexylcarbamate -butyl

6- (Fere-butoxycarbonylamino) hexanoic acid (197 mg, 850 pmol) was combined with DMF (10.9 ml) to give a colorless solution. 0- (Benzotriazol-1-yl) -W, W, W, W-tetramethyluronium tetrafluoroborate (TBTU, 300 mg, 936 pmol) and W, W-diisopropylethylamine (DIEA, 728 µl, 4.25 mmol) were added with stirring in an inert atmosphere. Then, 1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine (example 1c, 304 mg, 850 pmol) and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo, dissolved in ethyl acetate (5 ml), stirred for 1 min with cold sodium hydroxide solution (1 N) and dried by passing through ChemElut® (10 g). The organic phase was concentrated in vacuo again and the residue was purified by flash chromatography (silica gel, 10% methanol in dichloromethane) to give the title compound (0.135 g, 23%) as a light brown oil; LCMS (UV peak area, ESI) 83%, 571.5 (MH +).

Example 7

(E) -ethyl 3- (4-amino-1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c1quinolin-7-yl) acrylate a) 5-amino-2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -1H-imidazole-4-carbonitrile

Triethylamine (5.28 mL, 37.9 mmol) was added with stirring to a suspension of 4-methylbenzenesulfonate of 2-aminomalononitrile (8g, 31.6mmol) in THF (120ml) to give a light brown solution. 1,1,1,2-tetraethoxyethane (7.82 g, 37.9 mmol) was added and the reaction mixture was stirred under argon at reflux temperature. After 4 h, an additional 2.3 g of 1,1,1,2-tetraethoxyethane was added and the mixture was heated for another 2 h. The mixture was allowed to cool to room temperature, triethylamine (5.28 ml, 37.9 mmol) and 1-amino-2-methylpropan-2-ol (3.63 ml, 37.9 mmol) were added and the mixture was stirred reaction overnight. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (200 ml, 2x150 ml) and sodium bicarbonate solution (2M, 100 ml). The organic phases were combined, dried over MgSO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give the title compound after a step of crystallization with heptane (4.47 g, 59%) as a white crystalline solid; LC-MS (UV peak area, ESI) 100%, 239.1514 (MH +).

b) 2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -5-iodo-1H-imidazole-4-carbonitrile

Diiodomethane (14.5 ml, 180 mmol) was added under argon with stirring to a suspension of 5-amino-2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -1H-imidazole-4-carbonitrile ( 4.36 g, 18.3 mmol) in chloroform (170 ml). The reaction mixture was heated to 80 ° C, a solution of isoamyl nitrite (9.86 ml, 73.2 mmol) in chloroform (30 ml) was added with a syringe pump over a period of 40 min and stirred mixing for another 30 min at 80 ° C. After cooling to room temperature, the mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 20% to 50% ethyl acetate in heptane) to give the title compound (3.66 g, 57 %) as a brown oil; LC-MS (UV peak area, ESI) 90%, 350.0374 (MH +).

c) Methyl 3-amino-4- [5-cyano-2- (ethoxymethyl) -3- (2-hydroxy-2-methylpropyl) -1H-imidazol-4-yl] benzoate

In an inert atmosphere, 2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -5-iodo-1H-imidazole-4-carbonitrile (3.66 g, 10.5 mmol) was combined with dimethoxyethane (43 ml) to give a light brown solution. To this solution were added Pd (OAc) ² (118 mg, 524 pmol), triphenylphosphine (275 mg, 1.05 mmol) and 3-amino-4- (4,4,5,5-tetramethyl-1,3 Methyl, 2-dioxaborolan-2-yl) benzoate (4.36 g, 15.7 mmol) with stirring. Finally Na2CO3 (2M, 15.7 ml, 31.4 mmol) was added. The reaction mixture was heated to 100 ° C and stirred for 1 hour. After cooling to room temperature, the mixture was partitioned between ethyl acetate (70 ml, 2x50 ml) and water (70 ml). The organic phases were combined, dried over MgSO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give the title compound (2.79 g , 71%) as a light brown foam that was used in the next step without further purification.

d) Methyl 4-amino-2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinoline-7-carboxylate

Methyl 3-amino-4- (4-cyano-2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -1H-imidazol-5-yl) benzoate (2.79 g, 7, 49 mmol) with a solution of HCl in dioxane (4M, 56.2 mL, 225 mmol) to give an orange solution. The reaction mixture was heated to 90 ° C under argon with stirring. After 1 hr at 90 ° C, the mixture was cooled to room temperature and concentrated in vacuo to obtain a beige solid. The solid was dissolved in ethyl acetate (500 ml), washed with a mixture of water (100 ml) and a saturated solution of sodium bicarbonate (250 ml). The aqueous phase was extracted with ethyl acetate (2x250 ml), the organic phases were combined, dried with MgSO ⁴ and concentrated in vacuo to obtain a yellow solid (3.05 g). The solid material was recrystallized from ethyl acetate / heptane to give the title compound (2.4 g, 86%) as a light yellow solid; LC-MS (UV peak area, ESI) 99%, 373.1884 (MH +).

e) Methyl 2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinoline-7-carboxylate

The title compound was synthesized analogously to Example 1a, using 4-amino-2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinoline-7- methyl carboxylate as the starting material and isolated (0.77 g, 96%) as a light brown solid; Cl-MS (UV peak area, ESI) 96%, 615.4 (MH +).

f) 2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinoline-7-carboxylic acid

Sodium hydroxide solution (1 N, 3.51 mL) was added to 2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -4- (tritylamino) -1H-imidazo [4,5-c ] methyl quinoline-7-carboxylate (540 mg, 878 pmol) dissolved in THF (6.21 ml) and methanol (621 µl). The reaction mixture was stirred for 120 hours at room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (30 ml) and cold 1M HCl solution (5 ml). The aqueous layer was extracted with ethyl acetate (2x 50 ml). The organic layers were washed with water (20 ml) and brine (20 ml), combined, dried over MgSO4, and concentrated in vacuo to obtain the title compound (0.499 g, 94%) as a white solid; LC-MS (UV peak area, ESI) 99%, 601.3 (MH +).

g) 2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -W-methoxy-W-methyl-4- (tritylamino) -1H-imidazo [4,5-c] quinoline-7-carboxamide

To a solution of 2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinoline-7-carboxylic acid (484 mg, 741 pmol ) in DMF (5.19 ml) under an inert atmosphere was added TBTU (357 mg, 1.11 mmol), DIEA (388 μl, 2.22 mmol) and W, 0-dimethylhydroxylamine hydrochloride (108 mg, 1 , 11 mmol) with stirring. The reaction mixture was stirred for 1 hr at room temperature and then the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (40 ml, 2x20 ml) and water (40 ml). The organic phases were washed with water (2x20 ml), combined, dried over MgSO4, concentrated in vacuo and purified by flash chromatography (silica gel, 50% to 100% ethyl acetate in heptane) to give the title compound (0.53 g, quant.) as a white foam; LCMS (UV peak area, ESI) 92%, 644.4 (MH +).

h) 2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinoline-7-carbaldehyde

To a solution of 2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -W-methoxy-W-methyl-4- (tritylamino) -1H-imidazo [4,5-c] quinoline-7- carboxamide (520 mg, 808 pmol) in THF (7 ml) in an inert atmosphere was added with stirring at 0 ° C a solution of lithium aluminum hydride in THF (1 M, 404 µl, 404 pmol). The mixture was stirred 1 h at 0 ° C, saturated ammonium chloride solution (10 ml) was added slowly and finally water (20 ml) and ethyl acetate (30 ml) were added. The phases were separated, the aqueous layer was extracted with ethyl acetate (30 ml) and the organic phases were washed with water (20 ml), combined, dried with MgSO4, and concentrated in vacuo to give the title compound. (0.49 g, quant.) As a white foam (LC-MS (UV peak area, ESI) 83%, 585.4 (MH +)) that was used in the next step without further purification.

i) (E) -3- [2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinolin-7-yl] prop Ethyl -2-enoate

(Carbethoxymethylene) triphenylphosphorane (422 mg, 1.21 mmol) was added to a solution of 2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -4- (tritylamino) -1H-imidazo [4.5 -c] quinoline-7-carbaldehyde (472 mg, 808 pmol) in dichloromethane (8 ml) under argon. The reaction mixture was stirred for 20h at room temperature and concentrated in vacuo. Crystallization from dichloromethane and diethyl ether yielded the title compound (0.399 g, 75%) as a white solid, LC-MS (UV peak area, ESI) 89%, 655.4 (MH +).

j) (E) -3- [1- [2- [2- (tert-butoxycarbonylamino) ethoxy] -2-methylpropyl] -2- (ethoxymethyl) -4- (tritylamino) -1H-imidazo [4,5-c] ethyl quinolin7-yl] prop-2-enoate

The title compound was synthesized analogously to Example 1b, using (E) -3- [2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -4- (tritylamino) -1H-imidazo [4 Ethyl, 5-c] quinolin-7-yl] prop-2-enoate as starting material and isolated (0.28 g, 42%) as a white solid; LC-MS (UV peak area, ESI) 76%, 798.6 (MH +).

k) (E) -3 [4-amino-1- [2- (2-aminoethox¡) -2-methylpropyl1-2- (ethoxy¡met¡l) ¡m¡dazo [ Ethyl 4,5-c1qu¡nol¡n-7-¡l] prop-2-enoate

The title compound was synthesized analogously to Example 1c, using (E) -3- [1- [2- [2- (ferc-butoxycarbonylamino) ethoxy] -2-methylpropyl] -2- (ethoxymethyl) -4- (tritylamino) ) Ethyl -1H-imidazo [4,5-c] quinolin-7-yl] prop-2-enoate as starting material and isolated (21 mg, 34%) as a white solid; CL-Em (UV peak area, ESI) 93%, 456.4 (MH +).

Example 8

Ethyl 3- (4-amino-1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7-yl) propanoate hydrochloride

a) 3- [1- [2- [2- (tert-butoxycarbonylamino) ethoxy] -2-methylpropyl] -2- (ethoxymethyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinolin- Ethyl 7-yl] propanoate

10% palladium on carbon (100 mg, 940 pmol) in ethanol (10 ml) was added to a suspension of 3- (1- (2- (2- (tert-butoxycarbonylamino) ethoxy) -2-methylpropyl) -2- ( (E) -ethyl ethoxymethyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinolin-7-yl) acrylate (280 mg, 351 pmol) in ethyl acetate (30 ml). The mixture was stirred for 6 h under an atmosphere of hydrogen at room temperature, filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel-NH ² , 0% to 100% ethyl acetate in heptane) to give the title compound (0.163 g, 58%) as a white solid; LC-MS (UV peak area, ESI) 74%, 800.5 (MH +).

b) Hydrochloride____ of____ 3- (4-amino-1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7-yl) propanoate ethyl

The title compound was synthesized analogously to Example 1c, using 3- [1- [2- [2- ( tert- butoxycarbonylamino) ethoxy] -2-methylpropyl] -2- (ethoxymethyl) -4- (tritylamino) - Ethyl 1H-imidazo [4,5-c] quinolin-7-yl] propanoate as a starting material and isolated (15 mg, 56%) as a white solid; LC-MS (UV peak area, ESI) 93%, 458.4 (MH +).

Example 9

Ethyl 3- (4-amino-1- (2- (2-aminoacetoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7-yl) propanoate a) Ethyl 3- [4- [bis (benzyloxycarbonyl) amino] -2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinolin-7-yl] propanoate

To a suspension of ethyl 3- (4-amino-2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinolin-7-yl) propanoate hydrochloride (300 mg, 665 pmol), DMAP (15 mg, 123 pmol) and DIEA (1.86 ml, 10.6 mmol) in dichloromethane (6 ml), benzyl chloroformate (380 µl, 2.66 mmol) was added ). The reaction mixture was stirred at room temperature for 20 h, more benzyl chloroformate (908 60 µl, 5.32 mmol) was added and stirring continued for another 6 h. The mixture was then poured into dichloromethane (50 ml), extracted with HCl (1M, 20 ml) and water (20 ml). The aqueous layer was extracted with dichloromethane (50 ml), the organic phases were combined, dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give the title compound (0.459 g, quant.) As a colorless oil; LCMS (UV peak area, ESI) 86%, 683.5 (MH +).

b) 3- [4- (benzyloxycarbonylamino) -1- [2- [2- (dibenzylamino) acetyl] oxy-2-methylpropyl] -2- (ethoxymethyl) -1H-imidazo [4,5-c1quinolin Ethyl -7-ll1propanoate

To a suspension of Ethyl 3- (4- (bis (benzyloxycarbonyl) amino) -2- (ethoxymethyl) -1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4.5 c] quinolin-7-yl) propanoate 300 mg, 439 pmol), 2- (dibenzylamino) acetic acid (337 mg, 1.32 mmol) and DMAP (107 mg, 879 pmol) in dichloromethane (4 ml) was added 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide (253 mg, 1.32 mmol) and molecular sieves (300 mg). After 1 hr of stirring at room temperature, the starting materials were dissolved, stirring was continued at room temperature for 6 h, and the mixture was allowed to stand over the weekend. The residue was diluted with dichloromethane (50 ml) and washed with HCl (1M, 20 ml) and water (20 ml). The aqueous phase was extracted with dichloromethane (50 ml), the organic phases were combined, dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give the title compound (182 mg, 52%) as a light yellow oil; LC-MS (UV peak area, ESI) 98%, 784.6 (MH +).

c) Ethyl 3- (4-amino-1- (2- (2-aminoacetoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7-yl) propanoate

3- (4- (benzyloxycarbonylamino) -1- (2- (2- (dibenzylamino) acetoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7- ethyl yl) propanoate (182 mg, 232 pmol) with ethyl acetate (20 ml) to give a light yellow solution. 10% palladium on carbon (600 mg, 232 pmol) was added and the mixture was stirred for 20 h at room temperature under H ² . The mixture was then filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 30% methanol in THF) to 27 mg of an impure sample which was further purified by preparative HPLC to give the title compound (6 mg , 5%) as a light yellow oil; LC-MS (UV peak area, ESI) 79%, 516.5 (MHCOO ').

Example 10

1- (2- (2-aminoethoxy) -2-methylpropyl) -2-pentyl-1H-imidazo [4,5-c] quinolin-4-amine

a) 2-methyl-1- (2-pentyl-1H-imidazo [4,5-c] quinolin-1-yl) propan-2-ol

To a solution of 1- (3-aminoquinolin-4-ylamino) -2-methylpropan-2-ol (CAN 129655-59-0, 0.94 g, 4.06 mmol) in dichloromethane (9.5 ml) in An inert atmosphere was added dropwise with stirring at room temperature over a period of 6 min, a solution of hexanoyl chloride (422 µl, 4.47 mmol) in dichloromethane (6.4 ml). After 3 h, additional hexanoyl chloride (192 µl, 2.03 mmol) was added and stirring continued for another hour and finally the mixture was concentrated in vacuo. The residue was redissolved in ethanol (13.5 ml) and, after the addition of sodium hydroxide solution (1M, 10.8 ml), the mixture was heated with stirring under argon to 90 ° C. After 75 min, the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was stirred with ethyl acetate (30 ml) and water (5 ml), dried by filtration over ChemElut® and the ethyl acetate was removed in vacuo. The residue was purified by flash chromatography (silica gel-NH ² , 0% to 100% ethyl acetate in heptane) to give the title compound (747 mg, 89%) as a yellow oil; LC-MS (UV peak area, ESI) 95%, 312.2 (MH +).

b) 2-methyl-1- (5-oxide-2-pentyl-1H-imidazo [4,5-c] quinolin-5-io-1-yl) propan-2-ol

To a solution of 2-methyl-1- (2-pentyl-1H-imidazo [4,5-c] quinolin-1-yl) propan-2-ol (457 mg, 1.36 mmol) in dichloromethane (21, 2 ml) was added with stirring 3-chloroperoxybenzoic acid (283 mg, 1.64 mmol) in one portion. The reaction mixture was stirred for 16 h at room temperature. The mixture was then partitioned between cold dichloromethane (50 ml) and sodium hydroxide solution (1M, 20 ml). The organic phase was washed with cold water (20 ml) and brine (20 ml) and the aqueous phases were extracted with dichloromethane (2x50 ml). All organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 20% methanol in dichloromethane) to give the title compound (360mg, 80%) as a light yellow solid; LC-MS (UV peak area, ESI) 99%, 328.2 (MH +).

c) 1- (4-amino-2-pentyl-1H-imidazo [4,5-c] quinolin-1-yl) -2-methyl-propan-2-ol

To a solution of 2-methyl-1- (5-oxide-2-pentyl-1H-imidazo [4,5-c] quinolin-5-io-1-yl) propan-2-ol (353 mg, 1, 08 mmol) in anhydrous dichloromethane (47.6 ml) was added benzoyl isocyanate (90%, 286 µl, 2.05 mmol) with stirring under argon atmosphere at room temperature. The reaction mixture was stirred at reflux temperature for 35 min. The mixture was then concentrated in vacuo. The residue was then combined with anhydrous methanol (17.0 ml) to give a white suspension. Sodium methoxide solution in methanol (1.7 ml, 9.16 mmol) was added and the mixture was stirred for 1 hr at 70 ° C. The mixture was then cooled to room temperature and the solvents were removed in vacuo. The residue was partitioned between ethyl acetate (30 ml) and water (15 ml), dried by passage through a ChemElut® cartridge and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 10% methanol in dichloromethane) to give the title compound (221 mg, 61%) as a white solid; LC-MS (UV peak area, ESI) 98%, 327.2185 (MH +).

d) 2-methyl-1- [2-pentyl-4- (tritylamino) -1H-imidazo [4,5-c] quinolin-1-yl] propan-2-ol

The title compound was synthesized analogously to Example 1a, using 1- (4-amino-2-pentyl-1H-imidazo [4,5-c] quinolin-1-yl) -2-methyl-propan-2- ol as starting material and isolated (230mg, 71%) as a white crystalline solid; LCMS (UV peak area, ESI) 99%, 569.3 (MH +).

f) N- [2- [1,1-dimethyl-2- [2-pentyl-4- (tritylamino) -1H-imidazo [4,5-c] quinolin-1-yl] ethoxy] ethyl] carbamate of tere -butyl

The title compound was synthesized analogously to Example 1b, using 2-methyl-1- [2-pentyl-4- (tritylamino) -1H-imidazo [4,5-c] quinolin-1-yl] propan-2 -ol as the starting material and isolated (306 mg, quant.) as a light yellow oil; LC-MS (UV peak area, ESI) 53%, 712.2 (MH +).

g) 1- (2-1,2-aminoethoxy) -2-methylpropyl) -2-pentyl-1H-imidazo [4,5-c] quinolin-4-amine

The title compound was synthesized analogously to Example 1c, using W- [2- [1,1-dimethyl-2- [2-pentyl-4- (tritylamino) -1H-imidazo [4,5-c] quinolin Tere-butyl -1-yl] ethoxy] ethyl] carbamate as starting material and isolated (30 mg, 36%) as a white solid; LC-MS (UV peak area, ESI) 98%, 370.2622 (MH +).

Example 11

1- (2- (2-aminoethoxy) -2-methylpropyl) -7-bromo-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine hydrochloride a) 1- [7- bromo-2- (ethoxymethyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinolin-1-yl] -2-methylpropan-2-ol

The title compound was synthesized analogously to Example 1a, using 1- (4-amino-7-bromo-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl) -2-methylpropan -2-ol as starting material and isolated (100mg, 88%) as a light brown crystalline solid; LC-MS (UV peak area, ESI) 95%, 637.3 (MH +).

b) N- [2- [2- [7-bromo-2- (ethoxymethyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinolin-1-yl] -1,1-dimethyl- tere-butyl ethoxyl] ethyl] carbamate

The title compound was synthesized analogously to Example 1b, using 1- [7-bromo-2- (ethoxymethyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinolin-1-yl] - 2-methylpropan-2-ol as starting material and isolated (20mg, 44%) as a white solid which was used without further purification in the next step.

c) 1- (2- (2-aminoethoxy) -2-methylpropyl) -7-bromo-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine hydrochloride

The title compound was synthesized analogously to Example 1c, using W- [2- [2- [7-bromo-2- (ethoxymethyl) -4- (tritylamino) -1H-imidazo [4,5-c] quinolin Tere-butyl -1-yl] -1,1-dimethyl-ethoxy] ethyl] carbamate as starting material and isolated (7 mg, 58%) as a white solid; LC-MS (UV peak area, ESI) 99%, 438.2 (MH +).

Claims (11)

1. A compound of formula

in which R1 is C ^1-7 alkyl or C ^1-7 alkoxy Cwalquilo; R2 is selected from the group consisting of hydrogen, halogen, C ^1-7 alkoxycarbonyl Cwalquilo C ^1-7 -alkenyl and C2-7 alkoxycarbonyl; R3 is hydrogen; R4 is selected from the group consisting of -O- (CH ² ) m-NHR5 and -O- (CO) - (CH2) n-NHR6, in which m is 2, n is 1, R5 is hydrogen and R6 is hydrogen; or pharmaceutically acceptable salts thereof. 2. A compound of formula I according to claim 1, wherein R1 is C1-7-alkyl C ^1-7. 3. A compound of formula I according to claims 1 or 2, wherein R1 is ethoxyethyl. 4. A compound of formula I according to any one of claims 1 to 3, wherein R2 is hydrogen. 5. A compound of formula I according to claim 1 selected from the group consisting of 1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine, 1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl) -2-methylpropan-2-yl 2- aminoacetate, (E) -3- [4-amino-1- [2- (2-aminoethoxy) -2-methylpropyl] -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7-yl] prop Ethyl -2-enoate, 3- (4-amino-1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7- yl) ethyl propanoate, 3- (4-amino-1- (2- (2-aminoacetoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7-yl ) ethyl propanoate, 1- (2- (2-aminoethoxy) -2-methylpropyl) -2-pentyl-1H-imidazo [4,5-c] quinolin-4-amine, 1- (2- (2-aminoethoxy) -2-methylpropyl) -7-bromo-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine, and pharmaceutically acceptable salts thereof. 6. A compound of formula I according to claim 1, which is 1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine, and pharmaceutically acceptable salts thereof. 7. A compound of formula I according to claim 1 selected from the group consisting of 1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl) -2-methylpropan-2-yl 2- aminoacetate, Ethyl 3- (4-amino-1- (2- (2-aminoethoxy) -2-methylpropyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-7-yl) propanoate, and pharmaceutically acceptable salts thereof. 8. A compound of formula I according to any one of claims 1 to 7 for use as a medicine. 9. A compound of formula I according to any one of claims 1 to 7 for use as a medicament for the treatment of cancers or autoimmune diseases or infectious diseases selected from the group consisting of viral diseases, bacterial diseases, fungal diseases and diseases parasitic. 10. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier and / or adjuvant. 11. A process for the manufacture of a compound of formula I as defined in claim 1, which process comprises a) reacting a compound of formula II

wherein R1, R2 and R3 are as defined in claim 1 and GP is a protecting group, with a compound of formula III

in which m is as defined in claim 1, under basic conditions, and removing the GP and Boc protecting groups under acidic conditions to obtain a compound of formula Ia

wherein R1 to R3 and m are as defined in claim 1, and optionally further coupling the compound of formula Ia with an alcohol or acid of formula R5-OH or an aldehyde of formula R5 = O to obtain a compound of formula Ic

wherein R1 to R3, m and R5 are as defined in claim 1 and, if desired, converting the obtained compound into a pharmaceutically acceptable salt, or b) reacting a compound of formula Il-a

wherein R1, R2 and R3 are as defined in claim 1 and GP 'is a protecting group, with a carboxylic acid of formula IV

wherein n is as defined in claim 1 and GP "is a protecting group, in the presence of an esterification agent, and removing the protecting groups GP 'and GP" with a mild reducing agent to obtain a compound of formula I-b

wherein R1 to R3 and n are as defined in claim 1, and optionally further coupling the compound of formula Ia with an alcohol or acid of formula R6-OH or an aldehyde of formula R6 = O to obtain a compound of formula Id

wherein R1 to R3, m and R6 are as defined in claim 1 and, if desired, converting the obtained compound into a pharmaceutically acceptable salt.